Synthesis and Characterization of Non-Steroidal Ligands for the Glucocorticoid Receptor: Selective Quinoline Derivatives with Prednisolone-Equivalent Functional Activity Michael J. Coghlan,* ,† Philip R. Kym, † Steven W. Elmore, † Alan X. Wang, † Jay R. Luly, † Denise Wilcox, † Michael Stashko, † Chun-Wei Lin, † Jeffrey Miner, ‡ Curtis Tyree, § Masaki Nakane, † Peer Jacobson, † and Benjamin C. Lane † Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, and Departments of New Leads Discovery and Endocrine Research, Ligand Pharmaceuticals, Inc., 10255 Science Center Drive, San Diego, California 92121 Received May 22, 2001 A novel class of functional ligands for the human glucocorticoid receptor is described. Substituents in the C-10 position of the tetracyclic core are essential for glucocorticoid receptor (GR) selectivity versus other steroid receptors. The C-5 position is derivatized with meta- substituted aromatic groups, resulting in analogues with a high affinity for GR (K i ) 2.4-9.3 nM) and functional activity comparable to prednisolone in reporter gene assays of glucocorticoid- mediated gene transcription. The biological activity of these novel quinolines was also prednisolone-equivalent in whole cell assays of glucocorticoid function, and compound 13 was similar to prednisolone (po ED 50 ) 2.8 mpk for 13 vs ED 50 ) 1.2 mpk for prednisolone) in a rodent model of asthma (sephadex-induced eosinophil influx). Introduction Glucocorticoids (GCs) have a pervasive role in human health and physiology. The endogenous members of this family, cortisol and cortisone (Chart 1), are involved in a broad spectrum of endocrine functions including metabolism of lipids, carbohydrates, and proteins, stress response, fluid and electrolyte balance, as well as maintenance of immunological, renal, and skeletal homeostasis. 1-5 Prompted by the isolation of GCs and identification of their structures in the mid 1930s, a monumental research effort in the 1940s and 1950s resulted in the discovery of newer, more potent ana- logues and an understanding of their biological proper- ties, especially antiinflammatory effects. Prednisolone 6 and dexamethasone 7 emerged as benchmark drugs during this era. Although GCs are associated with a variety of clinical side effects, they are used for a breadth of antiinflammatory therapies while the search has continued for newer, more selective analogues. Despite considerable chemical and biological investiga- tions, an understanding of the exact mechanism of action of these renowned molecules has only recently been uncovered. The discovery and cloning of intracel- lular receptors (IRs) 8-10 demonstrated that steroids act in association with specific members of this family. The glucocorticoid receptor (GR) 11 is a member of a rapidly growing family of intracellular steroid receptors 12 that regulate gene transcription. GCs act as the natural ligands for GR, and the resulting GR/ligand complex (GRC) regulates gene expression. Other steroid recep- tors such as estrogen (ER), 13 progesterone (PR), 14,15 mineralocorticoid (MR), 16 and androgen (AR) 17 also regulate transcription as complexes with their natural ligands, yet many of the natural and synthetic steroids bind to more than one member of this receptor family. This cross reactivity can result in undesired side ef- fects: in the case of GCs, cross reactivity with MR, AR, and PR can be problematic. 18,19 The GRC regulates gene transcription by two modes of action depicted in Figure 1. 20 When a steroid or other ligand L associates with GR in the cytosol, the resulting GRC is transported into the nucleus where it can regulate gene expression in either a monomeric or dimeric form. The antiinflammatory effects of GRC are believed to occur through the monomer, which adopts a conformation possessing an affinity for existing tran- * Address correspondence to this author: Michael J.Coghlan, Drop Code 0528, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, IN 46285. Phone: 317-651-1620. Fax: 317-433-3666. E-mail: coghlan_michael@lilly.com. † Abbott Laboratories. ‡ Department of Endocrine Research, Ligand Pharmaceuticals, Inc. § Department of New Leads Discovery, Ligand Pharmaceuticals, Inc. Chart 1 2879 J. Med. Chem. 2001, 44, 2879-2885 10.1021/jm010228c CCC: $20.00 © 2001 American Chemical Society Published on Web 08/02/2001